Go ahead and get started. Thanks everyone for joining. This is the Fireside Chat with Sana Biotechnology. Very happy to have with me, Steve Harr. Steve, thanks for joining us. Really appreciate it.
Yeah, thank you, Vikram.
Thanks, everybody, for joining, and I appreciate Morgan Stanley giving us the invitation.
Sure.
All these lights are very bright, very hard to see out there.
Before I forget, let me make sure to read this disclosure statement. "Therefore, important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.
Okay, can I do the same thing? We're gonna make forward-looking statements. We spent a lot of time on our risk factors. They're in our filings. Take a look at them. You know, they're quite educational.
Okay. Great. So, Steve, appreciate your time. Quite a lot to talk about within Sana's platform, within the pipeline. Maybe the best place to start is just to level set for everyone because I'm not sure where everyone is in their understanding of the platform. And just talk about the thesis that drove the formation of the company, some of the underlying science for the Hypoimmune platform, maybe a little bit on the fusogen platform, and then we can go into specifics on the program from there.
Sure. So, thanks. And, yeah, when we started the company, it was kind of around this basic belief, that one of the most transformational things that will happen in medicine over the next several decades is the ability to use cells and, modify genes as medicines. And, what we thought we would do is go after what we thought were the most readily tractable but important challenges, and it led us down two paths, right? And so, if we want to be able to transplant cells at scale, we just have to figure out how to overcome, allogeneic rejection. And if you put my cells into you, your immune system's gonna recognize them and kill them. And you can overcome that with autologous cells. There are only a few cells you can do that with, and it's very difficult to scale.
We can overcome that with, you know, immunosuppression, but that really isn't ever gonna work for a lot of patients. So this is fundamental to being able to, importantly, most importantly, to really turn pluripotent stem cells into a therapeutic category. It also will have, you know, broader applications. And so that led us down the path of creating this thing we call our Hypoimmune platform, which we'll get into the science behind that in a second. The second thing we want to be able to do is to modify genes inside the body. And so you can more or less do anything you want to a genome, to RNA in a Petri dish. And the real challenge is delivering the reagents to the cells inside the body.
And so we went after the goal of being able to deliver any payload to any cell, right, in a predictable and repeatable way. And so, a specific and repeatable way. And that led us down the path of this fusogen technology, which is the other technology. So those were the two founding elements, being able to overcome immune rejection, and then delivery. But with that, we've had to build some other capabilities. To really leverage the Hypoimmune platform, we need to understand the cells. So that's made us really build capabilities around T cells and also pluripotent stem cells. To really exploit the ability to deliver, we've had to really develop the technology to actually incorporate the genetic reagents into these virus-like particles, or VLPs. We call it genome modifications. That's kind of the technology we built the company around.
As it turns out, this hypoimmune technology, like we've been trying to transplant cells for, I don't know, 70, 80 years, and they're consistently rejected without immunosuppression. In fact, there's only one cell type we can really do that with, and that's red blood cells. We do readily, you know, do that. If we get this right, right, we think we can develop three different really important categories in the very near term, right? One is being able to make allogeneic CAR T cells to go after blood cancers. And our first drug is in human testing. Hopefully, we'll have some data later this year, and we'll continue to have a lot more data as we move forward.
And there we have three different CARs that we've licensed, where we think we have, you know, validated CAR, well, it's basically a validated payload and a platform we can deliver it with. And we can go after CD19 cancers, lymphoma, we can go after CD22 expressing cancers, which is really CD19 failures, and then myeloma with BCMA. It's gonna be a big category for the company. The second is taking these CAR T cells and going after autoimmune disorders. And, you know, it was about a year ago when the first presentation came around, around applying CAR T cells to autoimmune disorders. And if you haven't looked at the data, it's worth spending time with. It's, it, it's transformative. I mean, you've never seen people talk about potentially curing autoimmune diseases.
This is what we haven't talked about before. We'll file an IND in the first parts of 4Q. We'll be, and we'll go after multiple indications from the outset. We'll have an opportunity to have data, really, as we move through 2024 across a host of different indications. Then the third is being able to apply this technology to beta cells, right? And to hopefully create a single therapy where type I diabetics are euglycemic, meaning normal glucose levels, with no insulin and no immunosuppression. We'll get our first hint around whether that's possible, as early as hopefully the end of this year. That's a little bit around where that's going. We can get into how it works and why in a second, but that's what we've been up to.
Great. Great. Maybe we can talk about SC291-
Yeah
Y our CD19 program, just because I think it's top of mind for a lot of people, just because you've guided to initial data there by the end of the year. First question: How is this construct structurally different from a regular CD19 CAR?
Yeah.
What makes it engineered to be a Hypoimmune product?
Yeah. The autologous CAR T cells, they insert a single gene generally, right? It's the chimeric antigen receptor, and that's the CAR, right? It's got a, an antibody-like fragment that recognizes the tumor, and it's got a little, costimulatory domain, like a gas pedal, and then it's got the T cell signaling. So that everything has. What's different about this, and we're putting in an allogeneic CAR T cell, is we need to deal with two different problems. One is, if I put my T cells into you, I'm gonna try to kill you. And so we have to knock out the T cell receptor so that my T cell won't recognize your cells. All right? So that's part one. The second part is your immune cell is gonna try to kill my T cell. That's called host- versus- graft disease.
There, you have to deal with two elements of the immune system. The first is something called the adaptive immune system. That's B and T cells. We hear a lot about them, in particular, of late around vaccines. Okay? That's relatively easy to deal with. We knock out MHC class I and class II, and that's been known for a while. The problem is that actually was discovered hundreds of thousands of years ago by viruses and cancers, right? And so we evolved something called natural killer cells to deal with cells that don't express MHC class I and class II, and that's called part of the innate immune system. And that's been the real challenge for the field now for 20-30 years, and that's where overexpression of CD47 appears to turn off that entire arm of the immune system.
And, what we have shown is that, you know, we've solved the problem of transplant rejection for non-human primates. We've solved it for mice, we've solved it for humanized mice, and we really just need to see just that, all of that, you know, preclinical evidence translate into people. So really what's different between this and, like, a regular autologous CAR T cell is three different gene knockouts. We knock out TCR alpha. That's to deal with graft-versus-host disease. We knock out MHC class I, MHC class II, then we knock in CD47. So that's to deal with host-versus-graft disease. So it's five gene modifications. It's a very complicated manufacturing process, as you might imagine.
Sure, sure. Okay. That's helpful. Now, maybe staying on SC291, but a bit more of a tactical question. So good amount of focus on this initial data set. Just frame expectations for us in terms of what you're hoping to establish with this data. Which questions do you hope to be able to answer here, and which questions do you think are going to require further data set beyond this initial one?
So I kind of think you would just to peel back the onion of evidence, right? So what's the most important question for the company is, do the data we've seen in monkeys and mice and all the non-clinical data translate into people, right? And that's most of the risk. So the next question would be, "Okay, yes, you've done that." I'll tell you how we get to that. Do you guys make really good CAR T cells, right? Then the next set of data would be, okay, does that translate into clinical benefit, right? And then it's like, can you consistently manufacture it? Right, that would be kind of the 4 big questions. So question number 1, we have a limit, where you take a healthy volunteer's cells, and you gene-edit them. It turns out that not 100% of the cells get gene-edited.
It's about 80%-85% have all the gene edits. We can make lemonade because what happens here, what we know is that in every allogeneic CAR T cell to date, the immune system is suppressed. The cells, CAR T's, grow. The immune system comes back, and within a few days, all of the CAR T cells are gone. So what should happen here, if our drug works like we think it is, is that when the immune system comes back, instead of all of them going away, we'll go from 85% to 100% of the cells being fully edited. 'Cause then what you know is you have cell survival in the context of an intact immune system. So that's really, I think, most of the risk of the company, right?
Have you actually solved the problem of allogeneic transplant rejection? That's not a very complicated question to answer, right? You need to see cells grow, then you need to see the non-edited cells go away as the immune system comes back. Second level of evidence, do you make good CAR T cells? There, you probably want to see, you know, a nice level of complete responses, and then you want to see the cells persist for a while, right? Which is a combination of immunology and how well we make them. So that will take, you know, a decent amount of time, not forever. We should know the first question, hopefully, sometime this year. Second question, maybe, maybe not, right? Third question, you make good CAR T cells. What's gonna be on your label? What does your durable complete response rate look like?
That requires a while, right? 'Cause you need to have a lot of patients out at least six months, right? 'Cause three out of eight isn't different than three out of four, right? You need a lot of them. And so that's gonna be a year from now, right? Then the fourth question is, can you repeatedly manufacture and get comparable safety and efficacy? It's gonna take us a few years, right? So that, that's how I like to think about it. Let's figure out the biggest question. Does this immunology really work? 'Cause the probability is we make good CAR T cells, right? We have good people. The probability, if you make good CAR T cells, is it's gonna translate into a really nice clinical benefit, right? There's, there's not a lot of risk in those, it's not zero, but the real risk is upfront.
Sure. So to kind of summarize that, and correct me if I'm mistaken, anything here, sounds like this initial data set focused on responses, T cell persistence, durability, likely a next year type of event.
Might be. I just don't know what's gonna happen. I mean, we don't know when it's gonna happen, but the durability requires lots of patients out, three months plus.
Yeah.
Right? And this, this trial hasn't gone on that long.
Sure.
We get fortunate and, you know, it's a dose escalation study.
Right? You know, the approved CAR T cells are all kind of 100-150 million cells per patient.
Yeah.
Yeah, we're starting out at 60, then 120, then 200. It may be that with healthy volunteers, 60 million is more than enough… it may be because of all these gene edits, we need 200 million, right? And so I think we've captured the sandwich of where it's likely to reside. We just have to see how the data play out.
Got it. And you, I mean, you alluded to this point, but just to put a fine point on it, these modifications that you're making that are the foundation of the Hypoimmune platform, assuming the data trends well, things work out well, what are the complexities that would stop someone else from trying to do the exact same thing? Or how long would it take someone else to try to replicate what you've been able to do, assuming the data trends well?
Well, I'll start with, we have intellectual property, so they have to deal with that, right? You know, they would also... There's a lot of intellectual property across our supply chain. They have to deal with that, right? When you go to make five gene edits or gene modifications, there are a couple things that are true. Number one, it's a very complex supply chain, even if you get the intellectual property. And then you have to actually characterize what you do, right? Because you could easily have an off-target effect that's not good, right? When you're doing all this, or cells could not react well to all of the gene editing agents. And so it's a multi-year process to manufacture. You know, we have great intellectual property.
I think the best way to make sure that people, you know, have to grapple with the challenge is just execute. The best thing is execute and create clinical data and get out there and, and it will be very difficult to displace us unless you're meaningfully better, right? But, you know, we have a lot to protect us, but you can't say never say never. And I'm pretty sure that if it turns out that these three gene edits, gene modifications, are adequate to really overcome immune rejection, there's probably a different way to do it. Like, someone will figure out a different way to do it, right?
Right.
We'll just deal with it when it happens.
Sure. Okay.
There is no, you know, indelible monopoly in our industry.
Sure. Okay. When you think about your other CAR product candidates, and you've spoken previously about CD22, BCMA. I guess first, the housekeeping question, where do these programs stand right now? And then two, how should people think about the data flow that comes from CD19 and what the read-through is, if, in your opinion, if any, to these other CAR programs?
So I'll take three other near-term ones, or maybe two other very near-term ones. One is taking this CD19 CAR in autoimmune disorders, right? Previously, we said soon, we're now telling you we'll do it in a matter of weeks, right? We'll file an IND in multiple indications, right? Hopefully, you'll have a good bit of data as you move through 2024 across multiple indications. I think that is an area where, and what we're doing today, everybody compares us to autologous T cells, right? There, if it turns out that what we do really works, we'll, we'll, we'll just be in the lead, and, and we'll have a much more readily manufacturable process, right? That could be very, very, very valuable. We then have a CD22 CAR. That is a...
There's a CD22 CAR construct that's been validated in the autologous CAR setting. We licensed the rights to that, so it's a validated CAR construct. And all we do from CD19 to CD22 is change one little DNA sequence and one release assay. So one would think that if it works in one, it's your biologic risk is extraordinarily low, and it working in the, in the CD22 setting. So what we would do, our plan there is to go into CD19 CAR T cell failures. It's an area where today the average patient lives about four or five months. They don't have really any viable, you know, therapeutic alternatives, and it could actually be the first drug approved for the company. Because it will move, if it works, very, very rapidly.
And again, it's been validated in the autologous CAR setting. So BCMA, exact same thing, where we license a validated CAR in the autologous setting. It's a CAR construct from a company called IASO, where they have over 90, I think 96% MRD negativity rate at 28 days. Over 80% of patients still have undetectable cancer by MRD, the most sensitive measure, at one year. The data are, you know, best in class for the field. And all we do, again, is change a little construct in the DNA, and, you know, we'll reinsert, and then one release assay. So again, it should work there. You know, IND, you know, maybe next year. We've been reticent to... With all the preclinical work is done, but we need to do the manufacturing campaign. Takes a little over a year.
We want to have, you know, a nice, robust balance sheet to do that. And we have to be careful how quickly we invest in things. And so it could be starting this year. It may... As an IND, could be next year, could be in the following year, depending on how things play out. And, that's really, that's really about it.
Got it.
Right? So that's three different new CARs that could be in the clinic within the next 15 months, two within the next, call it, you know, INDs in the next quarter, right? And, hopefully, a lot of clinical data coming from them next year.
Okay. All right. We have around 10 or so minutes left. Maybe let's turn it to T1D, a good amount of focus here-
Sure.
-on that program as well. So, you've mentioned that there's an investigator-sponsored study in T1D, where there's some initial data expected by year-end. Just walk us through how that study is designed, what we can expect to learn, how people should interpret that data?
Yeah. So I think everyone recognizes, but type 1 diabetes is a disease where the immune system attacks a patient's own beta cell, and they get rid of them, and they no longer make insulin, right? Up until 100 years ago this year was a death sentence, and now you get insulin. And, you know, it's still a very large unmet need where if you have type 1 diabetes, it kind of takes over a patient's life in terms of what are they going to eat? How sick are they? How much they exercise? And, you know, you have about a 15-year shorter life expectancy, and in that time frame, patients have, you know, blindness, amputations, kidney failure, a whole bunch of other risks. So that's, that's the setting.
So what we've learned over time is that, one, you can take cadaveric islets from somebody that, somebody just recently died, isolate, you know, take the pancreas, isolate the islet cells and transplant those. And that with immunosuppression, patients can be insulin-free for a long period of time. It's been done thousands of times now in the world. Very difficult to find patients for whom lifelong immunosuppression is better than lifelong insulin, and very difficult to scale that manufacturing, right? The second thing we've learned is that you can take pluripotent stem cells and make them into islet cells, right? At least it's, you know, in a couple of patients, in the setting of profound immunosuppression and see, again, you know, the same type of you know, insulin-free normal glucose levels. The unknown question to really get to a cure is can you get rid of immunosuppression?
That's really what this study is testing. So our program in the long run is called SC451, and it's a gene-edited stem cell that we make into islets and then transplant. Our goal is very simple: one transplant, normal glucose for life, no insulin, no immunosuppression. So the real question is, can you get rid of immunosuppression? We've shown that, yes, you can in non-human primates. We've done this, right? Yes, you can in all of the animal models, including the one we create ourselves for autoimmunity in mice, right, or humanized mice. The question is, really, can you do it in people?
So what we're doing here is a center that does cadaveric islet transplants at a high level is sponsoring with the regulators a study where we will do our gene modifications on cadaveric islets and just transplant them in the patient, no immunosuppression, and see what happens. So the goal of the study is to see can we overcome allogeneic, so someone else's cells, and autoimmune rejection of cells. And that's really quick to learn, right? So if you were to transplant normal cells, unedited cells, they would be dead within about a week. So the goal is to see cell survival anytime beyond two weeks. Like our transplant immunologist, they said, "We're going to pop the champagne at two weeks." I asked them to have a beer, and I'd love to have it on it.
Like, it just feels better in a month, but there really isn't anything the immune system will come and get you after that, right? And, that's the primary goal. So how will you see if they're still alive? The simplest level of evidence and is actually just to image them, right? And say, "Okay, these cells are alive, and we're not seeing an immune response to them," right? That's really pretty good, and, you know, that, that's our first goal. The second is if you actually have enough functional cells, we should be able to see a protein called C-peptide. And the way that insulin is made in our cells is actually made in something called proinsulin, and then when it's secreted, you secrete insulin and C-peptide. Right, it gets cut.
And so every time we secrete insulin in our body, we also secrete C-peptide. So a type 1 diabetic has no C-peptide because they have no insulin. And so if you see C-peptide, and it's detectable and stable, you will know that not only have we, you know, overcome immune cells, I'm sorry, rejection, but we have functional beta cells in that patient, and they're stable. The third level of evidence would be that, hey, the patient's off insulin or doesn't need much insulin. So the doses we start at, it's reasonable to think we can get to number two. We might get to number three, right? No insulin, but that might be, that might be a bit too high of a bar. We'll see. And you'll know it very quickly because a week or two in, these cells should be dead.
So if they're alive and thriving, we've kind of done it. And that would be spectacular because at that point, considering you now know that a cure for type 1 diabetes is inevitable, right? Someone's already shown that you can do cadaveric islets with immunosuppression. Someone else has shown you can make islets from stem cells, and we will have shown you can get rid of the immunosuppression. So now it's just a matter of somebody to put it all together. We hope it's us. And our goal is an IND, you know, next year with the real product, but we'll see. But to really... Just to be clear, it's a long-winded explanation of this is a test of immunology. The question isn't can you make beta cells that will make enough insulin? That's been answered, yes.
It's a cooler study if you do, but ultimately, the goal here is to answer the immunology question.
Got it. Got it. Are there any major differences between the cells being used in the investigator-sponsored study and the SC451 product you'll be filing an IND on?
Yes.
What are those?
So one is, so you take the investigator-sponsored trial study. It's a pancreas is harvested from somebody who just died, right? And the islets are isolated and we gene modify the islets. And, you know, first off, they're mature islets. They were working in a person.
They're a differentiated cell. The second is we're going to have kind of a gemisch product. Some cells will be fully edited, right? We'll never be perfect at it. Some won't be, right? And those are the... and with the stem cell-derived product, what you have is you have the beauty, that you start with a single cell, where you know that you have all of the appropriate genetics in them, right? Gene modifications... And that, that's a pure product. But you're gonna then grow them from stem cells in the pipelines, right? And that's a, that's a challenging thing to do repeatedly at scale, right? And so there's, we have to make sure we really control the type of cell that comes out.
And to be clear, I think most of us don't really, we're not trying to make beta cells, but we're really making our glucose-sensitive insulin-secreting cells. That's what you test for, right? And we're trying to understand really how, yeah, because all the other functions of a beta cell we may or may not have.
Got it. Final question for you on SC451 then. Once you have an IND filed, what could a path to a pivotal program look like for that setting?
It's probably long, right? I mean, if you just look, the first part is there's a dose escalation portion of phase I.
Just generally, with all of these gene-modified cells, where some of the toxicity profile pops up a little later. In the early dose-finding studies, it's a reasonable interval between patients, right? Once you have that, I actually think, and you have a scaled, locked manufacturing process, it's pretty straightforward. I'm not even sure it's a randomized study, right? It's just you're gonna have people who would die, right, without insulin, and if you remove insulin and they have euglycemia, your product works. So just getting enough safety data and enough people. I mean, I don't think it's hundreds of people for years. I think it's pretty straightforward.
The hard part will be, I think the rate limiter might be, one, the dose-finding portion of it, and number two is there's no question our manufacturing process, as it sits today, is not adequate to supply the huge % of population of patients. So we will have to change the manufacturing process, and that will take time. Right?
Right. Okay, got it. We have three minutes left. Any questions from the audience? I'm not seeing any hands raised. If not, we can keep it going. Steve, maybe we can pivot from the programs then to kind of thinking about, like, the business and the portfolio a bit more comprehensively. So you've alluded to kind of capital considerations a couple of times throughout the conversation here. Are there parts of the pipeline that you think are just more inherently amenable to do?
More part... More what?
More just amenable to being partnered away or, establishing partnerships for?
Well, I think it's hard. Partnering away sounds like you're giving away your children, right?
Establishing a partnership.
I think I'll start with just we own 100% worldwide rights to everything in our portfolio. I don't think there's anything that over time, we will own a hundred... We will not partner, at least in some parts of the world. And just generally, what happens in partnerships, in my perspective at least, is, you know, small companies should lose based on every objective measure you can think of, and the only thing we have is, because we're smaller and more focused, we have crisper, faster decision making. So you end up doing a partnership too early, and you often end up with small company resources and big company decision making. So the later we can go, hopefully, the more we go towards big company resource, decision making, 'cause...
I'm sorry, resources, 'cause they have the global infrastructure we need, and hopefully, we can hold on to that small company decision making. So that's, like, you know, we don't want to do it too early because it can really, really bleed a lot of value out of the company. So but we will partner, you know, allogeneic CAR T cells in oncology, we will partner allogeneic CAR T cells in autoimmune disorders, and we will partner type one diabetes. There's no way we're gonna license those things and launch them globally. It just won't happen. So that's the great thing about partnerships is that they both bring in capital, and they decrease your burn, right? The downside to them is that they can slow a program down if you don't have complete strategic alignment and, you know, kind of synergistic capabilities and clarity around decision making.
We're in no rush to do it, but we will do them. We will do them across the portfolio.
Got it. Okay, great. Maybe I'll ask one final question to close us out, because we don't have too much time left. Let's touch on manufacturing maybe. Came up a couple times in the conversation.
Go with it.
Manufacturing?
Yeah.
So, just educate us a little bit about current capacity, how far that gets you for your current development plans.
Yes. So I'll start with, I don't think manufacturing generally in this space is so much about capacity as much as it's a scientific problem, and it's a process development, analytical development to really understand and control your product. Within, within the CAR T cells, if you look at the current manufacturing that we have, I don't think we need to do anything to launch this and be successful with, you know, with, with really nice cost structure, globally. So if you take a single manufacturing run and you assume in oncology, we use the middle dose, and in autoimmune, we use around the low dose. So for each manufacturing run, we would get about 450 patients in oncology and around 1,000 patients in autoimmune. That includes all the holdbacks for testing.
So that means if you run 100 batches per year which isn't, you know, that hard to imagine, that's 45,000 oncology patients or 100,000 autoimmune patients per year. So we get enough capacity from our current runs that we have drugs sitting on our shelves that we will use from the oncology setting for these autoimmune studies they're about to start. It's totally different than what people think about the oncology setting. This is scaled. It's ready to go. Pluripotent stem cells are different, right? There, you know, we're taking a process that can allow us, big enough to allow us predictably to make, hopefully, enough cells for, you know, a nice clinical study. You have to get to...
Imagine if we're really successful here, and we make enough drug product for 100,000 patients per year, and we do that for a decade, and it works, and it's a single treatment, it never goes away. After a decade, we have only treated 20% of the people in the U.S. and Europe. Okay? I can't understand how we're gonna get to enough manufacturing capacity to really satiate demand if it truly works like we hope it does. It may be we have to dose every decade or two, right? And that, again, is just, or every 5 years, and that really bleeds into the number of patients we can service. So that's a scientific challenge, like really trying to control an entire genome and cell as you move across trillions of divisions, right? And that's one we still have some work to do on.
If we've got the T cell thing nailed, a lot of work to do with the beta cells and other plates in our portfolio.
Got it. Okay, great. With that, we're actually at time. Steve, thanks so much for joining us. Really appreciate it.
Thank you, everybody.